HLA‐E/β2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression

Abstract

The host immune response plays a major role in colorectal carcinoma (CRC) progression. A mechanism of tumor immune escape might involve expression of the human leucocyte antigen (HLA)-E/b2m on tumor cells. The inhibitory effect of HLA-E/ b2m on CD81 cytotoxic T lymphocytes and natural killer (NK) cells is mediated by the main HLA-E receptor CD94/NKG2A. As the pathophysiological relevance of this mechanism in CRC remains unknown, this prompted us to examine, in situ, in a series of 80 CRC (i) the HLA-E and b2m coexpression by tumor cells, (ii) the density of CD81, cytotoxic, CD2441 and NKP461 intraepithelial tumor-infiltrating lymphocyte (IEL-TIL) and (iii) the expression of CD94/NKG2 receptor on IEL-TIL. These data were then correlated to patient survival. We provided (i) the in situ demonstration of HLA-E/b2m overexpression by tumor cells in 21% of CRC characterized by an overrepresentation of signet ring cell carcinomas, mucinous carcinomas and medullary carcinomas, (ii) the significant association between HLA-E/b2m overexpression by tumor cells and increased density of CD81 cytotoxic, CD2441 and CD941 IEL-TIL and (iii) finally, the unfavorable prognosis associated with HLA-E/b2m overexpression by tumor cells. Our findings show that HLA-E/b2m overexpression is a surrogate marker of poor prognosis and point to a novel mechanism of tumor immune escape in CRC in restraining inhibitory IEL-TIL.

Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

“…10,21 HLA-E expression has been observed in hepatocytes and appears to be increased in human HCC by Granulin-epithelin precursor, a hepatic oncofetal protein overexpressed in HCC. 22 By contrast, the enrichment of NKp46-and NKp30-positive NK-cells in HCCs with worse prognosis is in apparent contradiction with the activating function of these receptors, even though the above mentioned low expression of CD3z may reflect poor or absent receptor signaling.…”

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

“…The significantly 22,28,[34][35][36] Moreover, these alterations are not limited to activating receptors on NK cells. There are several studies that show that NK cell dysfunction is correlated with increased expression of the inhibitory receptor NKG2A and HLA-E. 26,37 Another study provided evidence of a significantly increased level of KIR3DL1-positive NK cells in patients with PC, GC and CRC. However, this increase was not associated with tumor progression.…”

“…20,29,32,37,[41][42][43] NKG2D ligands are often upregulated on a wide range of tumor cells in response to cellular stress during malignant transformation. However, as tumors progress, soluble MICA/B or ULBPs are often shed from the membranes of tumor cells.…”

Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8+ T‐cell recognition of stressed cells

“…Along with the fact that solid tumor cells are often exposed to hypoxia, and glucose metabolism within tumor cells is significantly altered, increased HLA-E expression has been observed in a wide variety of malignant tumors arising in colon, stomach, breast, ovary, cervix, kidney, and larynx as well as in melanoma and glioma [49][50][51][52][53][54][55][56]. In addition, positive correlations between an increase in HLA-E expression and poorer patient prognosis in colorectal and breast cancer patients have been reported [51,57,58].…”

“…1) [49][50][51][52][53][54][55][56]. We hence asked whether combined oxygen and glucose deprivation affect the surface expression of nonclassical HLA-E/ Qa-1 in addition to classical MHC I molecules.…”